The present invention relates to a device for receiving a chip shaped carrier having on one side a first surface which includes an active surface coated with an array of DNA snippets or the like, a second surface on a second side opposite to said first side, and an edge having a peripheral outer surface which extends between said first and said second surface, said active surface being adapted to be read by an electro-optical reading device.
The invention further relates to an analytical cartridge comprising a chip receiving device.
The invention further relates to a process for assembling a plurality of such chip receiving devices.
The invention further relates to a system for carrying out evaluation and/or monitoring methods involving electro-optical reading of an active surface of a chip shaped carrier.
The invention further relates to a method for positioning and fastening at least one second object in a first object, the first object being provided with a seat for said at least one second object.
Within the context of the instant invention a chip shaped carrier is a substrate, in particular a glass chip of e.g. squared shape having a thickness of e.g. 0.7 or 1.0 millimeter and a so called active surface, which is a surface coated with an array of different snippets of DNA, e.g. DNA oligonucleotide probes, located at known positions on that surface. Those snippets of DNA serve as probes for detecting DNA fragments with a complementary DNA sequence.
Within the context of the instant invention a receiving device for receiving such a DNA chip is in particular a one-way cartridge made of a plastic material, and a cartridge hosting a DNA chip is called an analytical cartridge.
DNA chips contained in such cartridges have a wide range of applications. For example, they may be used for studying the structure-activity relationship between different biological materials or determining the DNA-sequence of an unknown biological material. For instance, the DNA-sequence of such unknown material may be determined by, for example, a process known as sequencing by hybridization. In one method of sequencing by hybridization, sequences of diverse materials are formed at known locations on a surface of a chip, and a solution containing one or more targets to be sequenced is applied to that surface. The targets will bind or hybridize with only complementary sequences on the substrate. The locations at which hybridization occurs are detected with appropriate detection systems by labeling the targets with a fluorescent dye, radioactive isotope, enzyme, or other marker. Information about target sequences can be extracted from the data obtained by such detection systems.
By combining various available technologies, such as photolithography and fabrication techniques, substantial progress has been made in the fabrication and placement of diverse materials on chips of the above mentioned kind. For example, thousands of different sequences may be fabricated on a single substrate of about 1.28 square centimeter in only a small fraction of the time required by conventional methods. Such improvements make these substrates practical for use in various applications, such as biomedical research, clinical diagnostics, and other industrial markets, as well as the emerging field of genomics, which focuses on determining the relationship between genetic sequences and human physiology.
As commercialization of such chips becomes widespread, an economically feasible device and a method for receiving the chips with a high-throughput are desired.
Since the active surface of the chip, that is the surface thereof which is coated with the above mentioned diverse sequences, has to be accessible e.g. to optical detection means, e.g. in the case of fluorescence measurements, the chip has to be inserted into a wall of a one-way cartridge with its active surface facing the interior of the so-called process chamber within the cartridge, and with its opposite surface being accessible to the optical detection means.
For instance in the above mentioned method of sequencing by hybridization, processing of the coating on the active surface of the chip includes flooding of the process chamber of the cartridge with a solution containing one or more targets to be sequenced. Therefore, a liquid-tight connection between the chip and the one-way cartridge is necessary. In a known embodiment described in U.S. Pat. No. 5,945,334 this has been achieved under clean-room conditions by attaching the chip to a cavity of the cartridge by means of an adhesive, that is by gluing it into the cartridge. This known method for connecting the chip to the cartridge has serious disadvantages. First, the fluorescence of the adhesives used is so high that it substantially interferes and perturbates fluorescence measurements performed on the active surface of the chips and can even have saturating effect on a photomultiplier used for performing the fluorescence measurements. The adhesive has to be applied by a dispenser, which is not possible with any adhesive. Furthermore, the known adhesives are prone to develop or contain gases, which when freed would disturb the reactions. Another problem is occasioned by solvent present in the adhesive because the solvent may react with the DNA samples on the active surface. It has even be found that solvent negatively influence the properties of the glass surface of a chip shaped carrier, e.g. blurs it.
A further disadvantage of the known method for connecting the chip to the cartridge is that it is performed manually and is not suitable for being performed by automated means, because a very careful positioning within the receiving window of the cartridge is necessary. Furthermore, as the adhesive is applied thereafter, a second control, if the DNA chip is still in place, has to be performed. These operations are aggravated by the relatively large tolerances of the dimensions of the chips and their rather uneven edges.
A first aim of the invention is therefore to provide a device for receiving a chip of the above mentioned kind which avoids at least one of the above-mentioned disadvantages, and preferably all of it.
A second aim of the invention is to provide an analytical cartridge comprising a chip receiving device according to the invention.
A third aim of the invention is to provide a process for assembling a plurality of chip receiving devices according to the invention with a high throughput.
A fourth aim of the invention is to provide a system for carrying out evaluation and/or monitoring methods involving electro-optical reading of an active surface of a chip shaped carrier with avoiding at least one of the above mentioned disadvantages of prior art embodiments.
A fifth aim of the present invention is to provide a method for more conveniently placing a first object in a second object and to fasten it there.
According to the invention the above-mentioned first aim is attained with a device for receiving a chip shaped carrier having on one side a first surface which includes an active surface coated with an array of DNA snippets or the like, a second surface on a second side opposite to said first side, and an edge having a peripheral outer surface which extends between said first and said second surface, said first surface being adapted to be read by an electro-optical reading device, said device comprising
(a) a cartridge having an opening for introducing a liquid sample into said cartridge,
(b) said cartridge having a casing part which has an outer surface and an inner surface, a first cavity for receiving a chip shaped carrier,
(c) a layer of a sealing material which is reversibly transformable at least once from a solid state into a fluid state and which is provided in a sufficient amount to establish a liquid-tight bond between the inner surface of side walls of the first cavity and said peripheral outer surface of the edge of the chip shaped carrier when the latter is placed into said first cavity.
The main advantages of a chip receiving device according to the invention are due to the fact that the required liquid-tight connection of the chip to the cartridge is achieved by means of a solid sealing material which liquidifies when heated over a certain temperature and resolidifies when cooled. In the solid state, the sealing material constitutes a substantial part of the wall of a seat for a chip formed within the cartridge and thereby contributes to define the position of the chip when it is set in the socket. After the chip is positioned in the seat, the sealing material is liquidified by heating it and then fills the space between the solid walls of the seat and the chip. Since this happens when the sealing material is in liquid state, any irregularity of the edges of the chip does not impair the quality of the sealing.
Surprisingly, depending on the nature of the sealing material, the chip remains fluid-tight even if a sensible overpressure is applied, e.g. exerted by a liquid filled in the chamber of the cartridge.
A preferred sealing material is a material which is apt to be molten by applying heat and which resolidifies when cooled. A preferred sealing material is a hotmelt material, particularly a hotmelt adhesive, i.e. an adhesive fusible by heat, also known as xe2x80x9cthermoplastic adhesivexe2x80x9d.
According to the invention the above mentioned second aim is attained with an analytical cartridge which comprises a chip shaped carrier inserted in the first cavity of a chip receiving device according to the invention, wherein the sealing material fills the clearance between the walls of the first cavity and the chip.
According to the invention the above mentioned third aim is attained with a process for assembling a plurality of analytical cartridges according to the invention, which process comprises:
(a) providing a plurality of casing parts to an automated assembly line,
(b) providing a plurality of chip shaped carriers having each an active surface to said assembly line,
(c) positioning each of said chip shaped carriers within the first cavity of one of said casing parts by means of a first automatic apparatus,
(d) bonding each of said chip shaped carriers in said first cavity of said casing part, by liquidifying the sealing material.
The main advantages of a process according to the invention for assembling a plurality of chip receiving devices having the structure proposed by the instant invention are that such a process is adapted to be entirely performed using standard automated means and provides a high throughput.
According to the invention the above mentioned fourth aim is attained with a system for carrying out evaluation and/or monitoring methods involving electro-optical reading of an active surface of a chip shaped carrier, said system comprising
(a) a cartridge having an opening for introducing a liquid sample into said cartridge, and a casing part,
(a.1) said casing part being comprised in the cartridge and having an inner surface and an outer surface, a first cavity for receiving a chip shaped carrier, and means which provide access to a first cavity and thereby to said active surface of said chip shaped carrier, and
(a.2) said first cavity having a flat bottom surface and side wall surfaces which extend between said inner surface of said casing part and said bottom surface
(b) a sealing material being provided in said first cavity, said sealing material consisting of an at least once reversibly liquidifiable material, and
(c) a chip shaped carrier having an active surface which is adapted to be read by an electro-optical reading device, said chip shaped carrier being positioned in said first cavity of said casing part, and the sealing material filling the gap between the cavity walls, particularly its side walls, and the chip shaped carrier in order to hold the chip shaped carrier firmly and fluid-tightly in the cavity.
The main advantage of a system according to the invention is that it makes possible to carry out evaluation and/or monitoring methods involving electro-optical readings of an active surface of a chip shaped carrier of the above mentioned type and eliminates the above mentioned drawbacks of prior art equipment.
According to the invention the above mentioned fifth aim is attained with a method for positioning and fastening at least one second object in a first object, the first object being provided with a seat for the second objects, said method comprising
forming at least part of the walls of the seat, preferably the circumferential rim, from a solid material which is at least once reversibly liquidifiable, preferably a hot melt material,
placing the second objects into the seat, and
liquidifying the solid liquidifiable material so that the latter material attaches the first object to the second object and after resolidification establishes a bond between the first object and the second object.
According to this more general aspect of the invention, by use of hotmelt material, it is possible to produce solid objects providing seats, frames, cavities or the like, with the intention to place therein one or also more than objects and to readily fasten them therein. For this purpose, the rim of the seat is constituted at least to a sufficient part by a hot melt material. As the hot melt is solid under normal conditions, it is apt to be quite exactly adapted to the geometry of the second object(s), and the latter when placed into the seat, are exactly registered therein. Thereby, an additional control of exact position of the second object may be waived. After placing the second object(s) into the respective seat, the solid hotmelt is locally heated in order to render it liquid and to fasten the second object(s) in their seat.
Particularly advantageous is that the first object and the parts made of hot melt may be manufactured long time before they are used to receive and hold the second object(s). In other words, the hot melt, or more generally, the material which liquidifies when heated over a certain temperature and resolidifies again when cooled, is a solid part which is formed on the first object before it is used to form a bond between the second and the first object and which is molten, e.g. by irradiation using laser light, to behave as a glue and/or a fluid sealing material.
Preferred exemplary embodiments of the invention are described hereinafter more in detail with reference to the accompanying drawings, wherein